Approximately 100 million people worldwide suffer from type II diabetes, which is typically characterized by hyperglycemia due to excessive hepatic glucose production and peripheral insulin resistance, the root causes for which are as yet unknown. Hyperglycemia is considered to be the major risk factor for the development of diabetic complications, such as retinopathy, neuropathy, nephropathy and macrovascular disease.
Accordingly, hepatic glucose production is an important potential target for type II diabetes therapy. The liver produces glucose by glycogenolysis (breakdown of the glucose polymer glycogen) and gluconeogenesis (synthesis of glucose from 2- and 3-carbon precursors). Particularly, glycogenolysis is catalyzed in the liver, muscle and brain by tissue-specific isoforms of the enzyme glycogen phosphorylase. Prior studies suggest that glycogenolysis may make an important contribution to hepatic glucose output in type II diabetes. See WO 96/39384; WO 96/39385; EP 978279; Proc. Natl. Acad. Sci. USA 1998, 95, 1776-1781; J. Med. Chem. 1998, 41, 2934-2938. Thus, glycogen phosphorylase inhibitors are believed to be a useful therapeutic agent for treating type II diabetes and delaying the onset of diabetic complications by decreasing hepatic glucose production and lowering glycemia, while providing minimal risk of hypoglycemia and weight gain. See Id.
In recent years diabetes has been recognized as a component of Syndrome X (Metabolic or Dysmetabolic Syndrome), which consists of two or more of the often associated disorders—diabetes, hypertension, dyslipidemia (hypertriglyceridemia, low HDL and/or hypercholesterolemia) and obesity. Syndrome X is understood to result from the complex interplay of several metabolic, hormonal and physiologic abnormalities. Key among these is the hyperinsulinemia that often accompanies diabetes and has been associated with hypertension. It has been suggested that hypertension may be result in part from abnormal vascular growth and/or renal sodium retention caused by hyperinsulinemia. Because hyperinsulinemia is a compensatory response to hyperglycemia, treatments for diabetes that work by raising insulin levels (insulin, insulin secretagogues) treat hyperglycemia at the possible expense of promoting hypertension. However, treatments for diabetes operating by other mechanisms may decrease the need for insulin, thus ameliorating hyperinsulinemia and thereby potentially reducing the risk or progression of hypertension. The efficacy of glycogen phosphorylase inhibitors in lowering blood sugar is not dependent upon the production or delivery of insulin. Therefore, glycogen phosphorylase inhibitors may be effective in ameliorating hyperinsulinemia, while reducing the risk or progression of hypertension.
Both hypertension and glucose intolerance (hyperinsulinemia after a meal) are known to be independent risk factors for another component of Syndrome X, dyslipidemia. Therefore, treatments for diabetes that address hyperglycemia and reduce the need for insulin, such as glycogen phosphorylase inhibitors, offer the opportunity to treat not only diabetes and hypertension, but potentially dyslipidemia as well.
Further, glycogen phosphorylase inhibitors have been shown to decrease appetite for high fat foods in animal models of obesity (see WO 00/47206), and may thus be useful in the treatment of human obesity.
Therefore, by decreasing appetite for high fat foods, and by treating hyperglycemia without delivering or causing the production of insulin, glycogen phosphorylase inhibitors may be useful in treating or preventing, either directly or indirectly, all of the components of Syndrome X—diabetes, hypertension, dyslipidemia and obesity. See WO 96/39384, WO 96/39385, WO 00/47206.
Since the elements of Syndrome X are all risk factors for atherosclerosis and cardiovascular disease, glycogen phosphorylase inhibitors may be useful in treating, preventing or slowing the progression of atherosclerosis and cardiovascular disease.
Furthermore, atherosclerosis and cardiovascular disease increase the risk of ischemic events, both cardiac and non-cardiac, and both during normal day-to-day activities and in the perioperative setting. Glycogen phosphorylase inhibitors have been shown to reduce tissue damage during ischemic events (see U.S. Pat. No. 5,952,322, WO 99/43663, WO 96/39384, WO 96/39385), and therefore may be of use in minimizing the adverse impact of this often encountered consequence of atherosclerosis and cardiovascular disease.